Background: Breath testing may provide a non-invasive test for heart transplant rejection. Rejection elicits increased oxygen free radical (OFR) activity in the myocardium which degrades membranes by lipid peroxidation, evolving volatile organic compounds (VOCs) which are excreted in the breath. Phase 1 study design: 213 breath test were performed in heart transplant patients on the day of scheduled endomyocardial biopsy. Two pathologists independently graded the degree of rejection. Breath VOCs were assayed by gas chromatography and mas spectroscopy. Phase 1 study results: Oxidative stress was increased in heart transplant recipients. The breath tet was highly sensitive and specific for patients requiring treatment (Grades II and III rejection on biopsy). Experimental plan: The sensitivity and specificity of the breath test for heart trans in 1656 heart transplant patients at seven academic medical centers. rejection will be reevaluated in 1656 heart transplant patients at seven academic medical centers. The long-term aim of the research: If the Phase I findings are confirmed, widespread use of the breath test could identify heart transplant recipients at high risk of rejection. This test could dramatically reduce the number of endomyocardial biopsies performed every year, thereby reducing the mortality, morbidity and health-care costs of the procedure. PROPOSED COMMERCIAL APPLICATIONS: Breath testing could provide a non-invasive new tool for the early detection of heart transplant rejection, and reduce the need for routine endomyocardial biopsy.